Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19](C=O)=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:35][C:36](=[O:39])[CH2:37][CH3:38])C=CC=CC=1.[C:52]1(C)C=CC=CC=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19](/[CH:38]=[CH:37]/[C:36](=[O:39])[CH2:35][CH3:52])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(C=O)c3O2)cc1
Reactant: CCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCC(=O)/C=C/c1c([N+](=O)[O-])ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 5.00 g (12.2 mmole) of [(2R)-8-formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate in 200 mL of toluene was added 5.10 g (15.3 mmole) of 1-triphenylphosphoranylidene-2-butanone. The mixture was stirred at room temperature under nitrogen for 5 hours, after which time the solvent was removed in vacuum and the crude residue was column chromatographed on silica gel with methylene chloride as eluant to give 5.0 g of the (R)-enantiomer of the title compound as a yellow solid (m.p. 114° C.).
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3C=CC([CH:4]2[CH:3]=[CH:2]1)C3.C[SiH:12]([Cl:14])[Cl:13].CCCCCCCCCCCCCCCC>[Ni](Cl)Cl.C(P(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:5]1([CH2:6][SiH:12]([Cl:14])[Cl:13])[CH2:4][CH2:3][CH:2]=[CH:1]1
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C[SiH](Cl)Cl
Agent: Cl[Ni]Cl
Agent: CCCCP(CCCC)CCCC
Solvent: CCCCCCCCCCCCCCCC
Solvent: Cc1ccccc1
Product: Cl[SiH](Cl)CC1C=CCC1
Reaction time: 1 h
Yield: 285.7 %

Procedure:
As described in Example 2, 3.01 g (0.0228 mol) of dicyclopentadiene, 5.19 g (0.0451 mol) of methyldichlorosilane, 0.032 g (0.000247 mol) of nickel dichloride, 57 μL (0.000230 mol) of tributylphosphine and 4 mL of toluene and 2 mL of hexadecane were placed in a reactor. The reactor was sealed and the reaction was performed at 180° C. for 1 hour. Products were subject to simple vacuum distillation, thereby providing a mixture (11.8 g) of (2-cyclopentenyl)methyldichlorosilane (3.1 g, 38%), other unreacted reactants, toluene, hexadecane, and unidentified compounds.
Reaction SMILES: C[N:2]([C:24](OCC1C=CC=CC=1)=O)[N:3]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[C:4]([O:6]CC1C=CC=CC=1)=[O:5].CCOCC.[NH2:39][C:40]([CH3:44])([CH3:43])[CH2:41][OH:42].[C:45](=[O:48])([O-:47])[O-].[Na+].[Na+]>O>[C:4]([OH:6])(=[O:5])[C:45]([OH:47])=[O:48].[CH3:43][C:40]([NH:39][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:3][NH:2][CH3:24])=[CH:23][CH:22]=1)([CH3:44])[CH2:41][OH:42]
Reactant: O=C([O-])[O-]
Reactant: CN(C(=O)OCc1ccccc1)N(Cc1ccc(C(=O)Cl)cc1)C(=O)OCc1ccccc1
Reactant: CC(C)(N)CO
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CNNCc1ccc(C(=O)NC(C)(C)CO)cc1
Product: O=C(O)C(=O)O
Reaction time: 8 h

Procedure:
15.8 g. of 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)methyl]-benzoyl chloride were dissolved in 50 ml. of dry ether and, wherein 30 minutes within stirring, added dropwise to a solution of 3.3 g. of 2-amino-2-methyl-1-propanol and 3.6 g. of anhydrous sodium carbonate in 50 ml. of water. The solution was stirred overnight at 0°, the mixture diluted with 100 ml. of water and extracted 3 times with 100 ml. of methylene chloride each time. The united methylene chloride extracts were freed off the solvent in vacuo and the residue dissolved in 200 ml. of methanol, whereupon it was hydrogenated in the presence of 2 g. of 5% palladium-carbon. The colorless glacial material was transformed according to Example 20 into its oxalic acid salt. The crystalline crude material was recrystallized from methanol/acetonitrile, yielding 4-[(2-methyl-hydrazino)-methyl]-benzoic acid (1,1-dimethyl-2-hydroxy-ethyl)-amide oxalate as colorless platelets melting at 160°-162° (dec.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][N:15]3[CH:24]=2)=[CH:8][CH:7]=1.[CH2:25]=O.[CH3:27][NH:28][CH3:29]>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:25])[C:17]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][N:15]3[C:24]=2[N:28]([CH3:29])[CH3:27])=[CH:8][CH:7]=1
Reactant: CCCOc1ccc2nc(-c3ccc(OCCOC)cc3)cn2n1
Reactant: CNC
Reactant: C=O
Solvent: CC(=O)O
Product: CCCOc1nn2c(N(C)C)c(-c3ccc(OCCOC)cc3)nc2cc1C
Yield: 19.5 %

Procedure:
A mixture of 2-[4-(2-methoxyethoxy)phenyl]-6-propoxyimidazo[1,2-b]pyridazine (327 mg, 1 mmol), paraformaldehyde (200 mg, 6.65 mmol), aqueous dimethylamine (40% w/v, 1.0 mL, 8.5 mmol) and acetic acid (3 mL) was heated at 120° for 22 hours. The mixture was cooled and concentrated. The residue was dissolved in chloroform and extracted thrice with dilute (10%) hydrochloric acid. The combined extracts were basified with aqueous sodium hydroxide solution (25%), the resulting suspension chilled in ice and filtered by suction. The collected solid was washed twice with water and dried at the pump to provide Compound 98 (75 mg) as a beige solid. 1H n.m.r. (CDCl3) δ 1.07, t, J=7.4 Hz, 3H; 1.76-1.96, m, 2H; 2.32, s, 6H; 3.47, s, 3H; 3.74-3.82, m, 2H; 3.87, s, 2H; 4.14-4.22, m, 2H; 4.32, t, J=7.5 Hz, 2H; 6.66, d, J=9.5 Hz, 1H; 7.03, d, J=8.8 Hz, 2H; 7.77, d, J=10.2 Hz, 1H; 7.98, d, J=8.8 Hz, 2H. Mass spectrum (APCI+) m/z 385 (M+H, 60%), 340 (100).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[C:10]#[CH:11]>CN(C)C=O.[Cu-]=O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[C:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: C#CC(=O)OCC
Agent: O=[Cu-]
Solvent: CN(C)C=O
Product: CCOC(=O)C#Cc1ccc(O)cc1
Temperature: 110 °C
Reaction time: 15 h

Procedure:
To a solution of 4-iodophenol (22.3 g) in dimethylformamide (200 ml) were added 19.5 ml of ethyl propiolate and 14.8 g of copper (I) oxide, and the reaction solution was stirred at 110° C. for 15 hours. The reaction solution was cooled and then filtered through Celite, and the filtrate was vacuum-concentrated. The residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (4:1)), followed by recrystallization of the purified residue with hexane/ethyl acetate to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[Na].Cl[C:13]1[N:18]=[C:17]([NH2:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][C:13]2[N:18]=[C:17]([NH2:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CO)cc1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(COc2ccc([N+](=O)[O-])c(N)n2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 60.3 %

Procedure:
4-Methoxybenzyl alcohol (4.8 g, 34.7 mmol) was added to sodium (0.8 g, 34.7 mmol) in toluene (100 mL). After most of the sodium has dissolved 6-chloro-3-nitro-2-pyridineamine (5 g, 28.9 mmol) was added and the reaction was heated at 120° C. for 4 h. As there was still some starting material left, more anion of the 4-methoxybenzyl alcohol was prepared in a separate flask (0.6 g of sodium in 30 mL of toluene and 4 g of 4-methoxybenzyl alcohol were used) and added to the reaction at room temperature. The reaction was then stirred at room temperature for 5 h then water (250 mL) was added and the volume reduced to 200 mL. Diethyl ether was then added and the aqueous phase was extracted (3×500 mL). The combined organic phases were dried (MgSO4), filtered and evaporated. The residue was then chromatographed on silica gel, eluting with DCM to afford 4.8 g of the title compound (60%).
Reaction SMILES: [CH:1]1([CH:4]([CH:6]2[CH2:8][CH2:7]2)[OH:5])[CH2:3][CH2:2]1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:13][C@@H:14]1[O:16][CH2:15]1)(=O)=O.[H-].[Na+].CS(C)=O>O1CCCC1.O>[CH:1]1([CH:4]([CH:6]2[CH2:8][CH2:7]2)[O:5][CH2:13][C@H:14]2[CH2:15][O:16]2)[CH2:3][CH2:2]1
Reactant: OC(C1CC1)C1CC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: C1CC1C(OC[C@H]1CO1)C1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
Dicyclopropylmethanol (880 mg) obtained in Step 1 and (R)-glycidyl nosylate (3.05 g) were dissolved in tetrahydrofuran (7.3 ml), sodium hydride (471 mg) and dimethyl sulfoxide (1.5 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 5 hr. Water was poured into the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10) to give the title compound (760 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][N:13]3/[C:32](/[NH:44]C(=O)OCC3C=CC=CC=3)=[N:33]/C(=O)OCC3C=CC=CC=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:55]([OH:58])(=[O:57])[CH3:56].[H][H]>CO.[Pd]>[C:55]([OH:58])(=[O:57])[CH3:56].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][N:13]3[C:32](=[NH:33])[NH2:44])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(C(=N)N)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dibenzyl [(E)-{1-[1-(4-fluorophenyl)cyclobutyl]-7-{2-[(propylsulfonyl)amino]ethoxy}-3,4-dihydroisoquinolin-2(1H)-yl}methylylidene]biscarbamate (95 mg, 0.126 mmol) was dissolved in methanol (8 mL) under an atmosphere of nitrogen. Acetic acid (0.4 mL) was added followed by 10% palladium on charcoal (40 mg, 0.038 mmol). The nitrogen was replaced by one atmosphere of hydrogen and the reaction mixture was stirred at room temperature for 3 h. The catalyst was removed by filtration and the solution of the product was concentrated in vacuo. The product was dissolved in ethanol (0.5 mL) and water (15 mL) and was lyophilized. Yield: 61 mg (0.125 mmol, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:21])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[I:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[S:31])[CH:24]=1>C(#N)C>[I:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[S:31])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:21])[NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:18])=[O:19])=[CH:13][CH:12]=3)=[CH:6][CH:7]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc(NC(=S)Nc2ccc(S(N)(=O)=O)cc2)cc1
Reactant: S=C=Nc1cccc(I)c1
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(NC(=S)Nc2ccc(NC(=S)Nc3cccc(I)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of 4-(3-(4-aminophenyl)thioureido)benzenesulfonamide (0.322 g, 1.0 mmol) in acetonitrile was added 1-iodo-3-isothiocyanatobenzene (0.261 g, 1.0 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and water was added into the crude reaction mixture. The precipitate which formed was filtered, and dried to afford the title product as a white solid (0.452 g, 78%). 1H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 10.02 (s, 1H), 9.90 (s, 1H), 9.81 (s, 1H), 7.94 (t, J=1.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.68 (d, J=8.8 Hz, 2H), 7.48-7.41 (m, 5H), 7.12 (t, J=8.0 Hz, 1H); MS (ESI), 584 (M+H)+.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:33])[C@H:11]([N:16]([P@:24]([CH3:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][CH:13]([CH3:15])[CH3:14])C1C=CC=CC=1.CO.[H][H].CCCCCC>C(OCC)(=O)C.[Pd]>[OH:8][NH:9][C:10](=[O:33])[C@H:11]([N:16]([P@@:24]([CH3:32])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:25])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)C[C@H](C(=O)NOCc1ccccc1)N(Cc1ccccc1)[P@@](C)(=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: CC(C)C[C@H](C(=O)NO)N(Cc1ccccc1)[P@](C)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Benzyloxy-2(R)-[[(S)-methylphenylphosphinyl]benzylamino]-4-methylpentanamide (334 mg, 0.719 mmol) and 80 mg 10% Pd/C were evacuated in a flask. To this is added 10 mL methanol and a hydrogen atmosphere is introduced. The reaction is allowed to stir at room temperature for 2 hours at which time the reaction appears complete by TLC. The mixture is filtered through celite; the filtrate is collected and evaporated to give a white glassy solid. The product is dissolved in ethyl acetate and hexane is added dropwise until the product begins to precipitate to give N-hydroxy-2(R)-[[(R)-methylphenylphosphinyl]benzylamino]-4-methylpentanamide as colorless solid: MS-IS: m/z 375 [M+H]+, 397 [M+Na]+, 413 [M+K]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[CH3:14])=[O:6].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.O>CN(C)C=O>[CH3:14][C:8]1[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=1[C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(C(=O)CCCCl)c(C)c1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)CCCn2ccnc2)c(C)c1
Yield: 59 %

Procedure:
1-Chloro-4-(2,4-dimethylphenyl)-4-butanone (5.16 g) and imidazole (8.34 g) in dimethylformamide (10 ml) at 0° C. were stirred overnight at ambient temperature, then one day at 80° C. The resulting mixture was poured into water (200 ml), extracted with ether (3×75 ml) and the extracts were dried (magnesium sulfate) and evaporated. Chromatography of the product on silica gel eluting with 7% methanol in methylene chloride gave 3.5 g of 1-[4-(2,4-dimethylphenyl)butan-4-on-1-yl]imidazole.
Reaction SMILES: [CH2:1]([Zn]CC)C.[Cl:6]CI.C(OC([N:16]1[CH2:21][CH2:20][C:19](=[CH2:22])[CH:18]([OH:23])[CH2:17]1)=O)(C)(C)C>ClCCCl>[ClH:6].[CH2:22]1[C:19]2([CH2:20][CH2:21][NH:16][CH2:17][C@H:18]2[OH:23])[CH2:1]1
Reactant: ClCI
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1O
Reactant: CC[Zn]CC
Solvent: ClCCCl
Product: Cl
Product: O[C@@H]1CNCCC12CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36664.7 %

Procedure:
To a solution of diethylzinc (1.1 M solution in toluene, 37.5 ml, 0.04 mmol) in 1,2-dichloroethane (80 ml) at 0° C. was added chloroiodomethane (5.99 ml, 0.08 mmol) under Ar. This mixture was stirred for 15 minutes before a solution of 3-hydroxy-4-methylene-piperidine-1-carboxylic acid tert-butyl ester (J. Org. Chem. 2001, 66, 2487) (4.19 g, 19.6 mmol) in 1,2-dichloroethane (10 ml) was added, after which time the reaction was stirred for 0.5 h at 0° C. and then allowed to reach room temperature, stirring for a further 1 h. The reaction was then quenched by addition of saturated aq. ammonium chloride solution, separated, and the organic dried (Na2SO4) and concentrated. Purification by flash column chromatography (ethyl acetate/heptane 2:8-1:1) afforded the title product (2.4 g, 54%) as a crystalline solid MS: 228.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.[Cl-].[Na+]>CN(C=O)C>[CH3:13][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:12])[CH:9]=[C:10]([CH3:11])[C:2]=1[NH2:1]
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(Cl)cc(C)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1218.4 %

Procedure:
To a 500 mL round-bottom flask, 0.2 mol of 2-amino-3-methyl-5-chlorobenzoic acid having the structural formula of IV-5, 300 mL of DMF and 2.0 grams of potassium carbonate were added, stirred at room temperature for 0.5 hour, dimethyl sulfate was dripped, reacted at 110° C. for 7 hours, and cooled to room temperature, poured into a saturated sodium chloride solution, extracted with acetate ethyl, dried over anhydrous sodium sulfate, filtered and the solvent was removed to obtain a crude product, 35.2 grams of 2-amino-3-methyl-5-chlorobenzoic acid methyl ester having a structural formula of VIII-3 was obtained by column chromatography, and the yield was 88.4%;
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[O:20]([CH2:27][C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[CH2:27][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)COc1ccccc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin4-amine and phenoxyacetyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-phenoxyacetamide as an off white powder, m.p. 61.5° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.12 (t, J=6.0 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.62 (dd, J=8.4, 1.2 Hz, 1H), 7.44 (dt, J=7.5, 1.2 Hz, 1H), 7.29-7.21 (m, 3H), 6.96-6.88 (m, 3H), 6.62 (s, 2H), 4.60 (t, J=7.2 Hz, 2H), 4.42 (s, 2H), 3.16 (q, J=6.9 Hz, 2H), 1.83 (quintet, J=7.2 Hz, 2H), 1.47 (quintet, J=7.2 Hz, 2H);IR (KBr)3311, 3180, 2937, 1664, 1618, 1583, 1527, 1493, 1480, 1396, 1244, 755 cm−1; MS (EI) m/e 389.1844 (389.1852 calcd for C22H23N5O2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:24])=[N:22][N:23]=3)=[CH:15][CH:14]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH:26]1[CH2:30][CH2:29][N:28]([CH3:31])[C:27]1=[O:32]>CN(C=O)C>[CH3:24][C:21]1[O:20][C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:10]3[CH:9]=[C:4]([CH:3]=[C:2]([O:1][CH:26]4[CH2:30][CH2:29][N:28]([CH3:31])[C:27]4=[O:32])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:18][CH:17]=2)=[N:23][N:22]=1
Reactant: COC(=O)c1cc(O)cc(Oc2ccc(-c3nnc(C)o3)cc2)c1
Reactant: CN1CCC(Br)C1=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(OC2CCN(C)C2=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
To a stirring solution of Methyl 3-hydroxy-5-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]benzoate (4 g) (Intermediate 7) in dry DMF, 3-Bromo-1-methyl-pyrrolidine-2-one (4.12 g) (Intermediate 5) [J. Med. Chem., 1987, 30, 1995-98] was added under nitrogen atmosphere at room temperature in three portions at 4 h interval. The reaction mixture was stirred at room temperature for 16 h and then warmed to 45-50° C. for 3 h. The reaction was monitored by TLC. After completion, reaction mixture was diluted with ice cold water and extracted with EtOAc. All organic layers were combined and washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to get crude thick liquid product. Crude residue was chromatographed to yield pure compound (5.2 g).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14].Cl>O.CCOCC>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]([OH:14])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: O=Cc1ccccc1Cl
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: OC(c1ccc(Cl)cc1)c1ccccc1Cl

Procedure:
To 12.7 g. (0.52 moles) of magnesium turnings in 200 ml. of anhydrous ether is added 10.0 g. (0.052 moles) of p-bromochlorobenzene, and the mixture is warmed to reflux. When the Grignard reaction begins, the heat is removed and 80.0 g. (0.47 moles) of additional p-bromochlorobenzene in 80 ml. of ether is added dropwise as the refluxing continues. When the addition is completed, the reaction is heated at reflux for 2 hours, cooled, and 73.4 g. (0.52 moles) of o-chlorobenzaldehyde are slowly added. The reaction is refluxed for 2 hours, cooled and poured into iced water. The resulting mixture is made acidic with hydrochloric acid, and the organic phase is separated. The aqueous layer is extracted with ether, and the extract is added to the organic phase. This solution is washed with water, dried over anhydrous magnesium sulfate and concentrated to give an oily solid. The material is crystallized from petroleum ether to give 109.4 g. (83%) of the product, mp 68°-70°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][C:23]([C:22]1[CH:21]=[N:20][N:17]2[CH:18]=[CH:19][C:14]([N:9]3[CH2:10][C@H:11]([OH:13])[CH2:12][C@@H:8]3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:15][C:16]=12)=[O:25])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cccc(F)c3)nc12
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cccc(F)c3)nc12
Yield: 100 %

Procedure:
Prepared by the method described in Example 1 using 5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and tert-butyl amine to provide the final product as a white solid (24 mg, 100% yield). MS (apci) m/z=398.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:25]([CH3:26])=[N:24][N:23]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)[C:18]=3[N:19]=[C:20](Cl)[CH:21]=2)=[O:15])[C:10]([CH3:39])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH:41]1[O:46][C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1.[F-].[Cs+]>CN(C=O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:25]([CH3:26])=[N:24][N:23]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)[C:18]=3[N:19]=[C:20]([C:50]3[CH:51]=[CH:52][C:47]([O:46][CH:41]4[CH2:42][CH2:43][CH2:44][CH2:45][O:40]4)=[CH:48][CH:49]=3)[CH:21]=2)=[O:15])[C:10]([CH3:39])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(C2CCCCO2)c2nc(Cl)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3(C)c3ccccc3)c12
Reactant: OB(O)c1ccc(OC2CCCCO2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OC4CCCCO4)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3(C)c3ccccc3)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 936785.19 %

Procedure:
4-[6-Chloro-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-3-methyl-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester (255 mg) and 4-(tetrahydro-2H-pyran-2-yloxy)phenylboronic acid (153 mg) were dissolved in DMF/toluene (v/v=1/1, 7.5 mL). After inertisation of the mixture with argon; cesium fluoride (140 mg) and tetrakis(triphenylphosphine)palladium(0) (27 mg) were added. The mixture was stirred at 100° C. overnight. The mixture was filtered through a 0.2 μm membrane syringe filter, the filtrate was diluted with ethyl acetate and washed three times with water (15 mL each) and once with brine (10 mL). The organic phase was dried over magnesium sulfate and concentrated. The residue was absorbed on silica and purified by flash chromatography (heptane/ethylacetate v/v=1/1). 3000 g (94%) of the title compound were obtained.